It has been known since the 1950s that hypoxic tumor cells require up to 3 times the radiation dose compared to aerobic cells for equal toxicity. Because the total radiation dose administered is limited by the tolerance of normal adjacent tissues, the search for approaches to overcome the "hypoxia problem" has dominated radiation biology research for the last half century. One of the major limitations to attacking this problem has been the inability to identify and quantitate the presence of hypoxic cells in individual patients. In the last decade, the availability of the Eppendorf needle electrode technology has allowed data to be obtained on tumor tissue oxygenation in patients. Such studies have demonstrated hypoxia to negatively influence outcome in cervix, sarcomas and head and neck cancers. There is also substantial evidence that hypoxia exists and is biologically relevant in malignant brain tumors. The overall goal of our clinical hypoxia program is to determine whether the presence, levels and patterns of EF5 binding are important in the prognosis and therapy response of cancer patients. Our interests include patients with sarcomas, head and neck squamous cancer, cervix cancer and now, patients with brain tumors. In the studies proposed herein, we will study EF5 binding in patients with de novo supratentorial malignant gliomas (SMG). Concurrent studies in the same patient group using the Eppendorf needle electrode will serve as a bridge to previously published work. We will determine the relationship between EF5 binding and clinical outcome in patients with glioblastoma multiforme (GBM) versus non-GBM histologies. To better understand the pathophysiology of MG, we will study the presence and levels of various additional biomarkers. These studies are the necessary preliminary studies towards non-invasive studies of hypoxia in brain tumors. These non-invasive studies will be based on Positron Emission Tomographic (PET) imaging of 18F-EF5 followed by hypoxia-specific treatment interventions. 18F-EF5 has been synthesized and studied in animal tumors by our group. The necessary additional pre-clinical studies and applications for permits for these PET studies are ongoing at the University of Pennsylvania (PENN). We project that we will be able to institute clinical EF5 PET studies at PENN in patients with brain tumors in approximately 2 years, corresponding to the time that much of the data from the studies proposed herein will mature.